A REVIEW ON INDOLOTRIAZINE DERIVATIVES IN MEDICINAL CHEMISTRY: ADVANCED APPROACHES IN SYNTHESIS, BIOLOGICAL ACTIVITIES, AND COMPUTATIONAL INSIGHTS

Abstract

Indolotriazine (ITZ) derivatives have emerged as having immense potential in fused heterocyclic compounds with significant prospects in medicinal chemistry due to the synergistic combination of indole and triazine pharmacophores, which contribute to various biological and pharmacological activities. This review comprehensively summarizes recent advances in the synthetic methodologies, structural characterization, biological activities, and molecular docking studies of ITZ derivatives with an emphasis on their therapeutic potential. This review is based on a comprehensive analysis of more than 150 indexed research articles published during 1994–2025. Several synthetic techniques have been employed, such as conventional reactions (e.g., cyclization and controlled reactions; one-pot multicomponent synthesis; microwave-assisted synthesis; and green chemistry approaches, e.g., solvent-free, eco-friendly, etc.), which were comparatively discussed. Structural characterization techniques include infrared, nuclear magnetic resonance, mass spectrometry, thin-layer chromatography, high-performance liquid chromatography, and X-ray. Biological activities and ligand–protein interactions were further evaluated using in silico methods to validate the results obtained. Comparative analysis of synthetic methodologies revealed that microwave-assisted and green synthetic approaches offer improved reaction efficiency, selectivity, and yield. Structure– activity relationship studies demonstrated that the nature and position of substituents significantly influence biological activity and target selectivity. ITZ derivatives exhibited broad-spectrum pharmacological activities including anticancer, antimicrobial, anti-inflammatory, antidepressant, and antidiabetic effects through mechanisms involving apoptosis induction, enzyme inhibition, cytokine suppression, and modulation of neurotransmitter pathways. Important therapeutic targets identified include serotonin transporter, monoamine oxidase-A, dipeptidyl peptidase-4, α-glucosidase, and cyclooxygenase-2. Molecular docking studies further demonstrated favorable protein–ligand interactions mediated through hydrogen bonding, hydrophobic interactions, and π–π stacking. The stability and reliability of the docked complexes were further validated by root mean square deviation analysis using PyMOL and molecular mechanics/generalized born surface area binding free-energy calculations performed with HawkDock Server V2, confirming the favorable binding affinity and structural stability of the ligand–protein complexes. These findings suggest that ITZ derivatives provide a promising framework for the design of multifunctional therapeutic agents and offer considerable scope for future research and drug development.